We have identified a spontaneous mouse mutant (now maintained on an A/J inbred strain) that develops eosinophilic vasculitis in multiple organs. As disease progresses, the heart develops eosinophilic myocarditis, extensive fibrosis and right ventricular dilated cardiomyopathy, with mutant mice dying of heart failure (HF) by 14 weeks old. These pathologies overlap those for patients diagnosed with eosinophilic granulomatosis and polyangiitis, EGPA (also known as Churg-Strauss Syndrome). EGPA is a rare vasculitis affecting small- to medium-sized vessels, typically associated with asthma, peripheral and tissue eosinophilia, upper respiratory symptoms, and clinical signs of systemic vasculitis. Cardiac involvement is well-known, with prevalence ~60%. In fact, heart disease is linked with poor prognosis, accounting for ~50% of EGPA-related deaths. Delayed diagnosis can lead to rapid health decline, but patients identified early in the disease respond well to steroids and immunosuppressant drugs. Consequently, knowledge gained from this mouse mutant line has potential not only to improve quality of life for these patients, but to radically impact morbidity and mortality. The etiology of EGPA is unknown, but is expected to involve many genes. Besides preliminary work on the pathology of this mutant, we sought to map chromosome regions for genes linked to EGPA/HF. HF seen in maintenance lines of the mutant was consistent with 2 genes segregating for the trait. But results of our initial mapping attempts with C57BL/6J mice indicated one or more additional genes were segregating. To explain a disparity in the number of genes involved, we posited that a de novo mutation in an immunoregulatory gene, together with existing A/J- variants, leads to disease. Two aims are proposed: 1) Critically assess the mutant mouse line to establish as a valid model of EGPA/HF. We will characterize the line to differentiate features of EGPA from those for the hypereosinophilic syndromes or two similar vasculitides with overlapping clinical characteristics. And, since EGPA is highly associated with allergic asthma, we will further test the hypothesis that allergen inhalation can trigger disease development. 2) Map the EGPA/HF trait in this mutant line; identify and begin to evaluate top candidate genes. A backcross breeding strategy was selected over F2 crosses to increase the rate of affected mice, and DBA and SJL strains will be used to test a role for natural A/J mutations in hemolytic complement (C5) and/or dysferlin (Dysf) in EGPA, respectively. The proposed backcross strategy will markedly increase the rate of affected mice generated for mapping. We expect 3-4 dozen affected recombinants from different strain? pair combinations will allow us to map the key loci to high resolution and, with available exome and RNA-Seq data already in hand, to quickly find excellent candidate genes. When validated as a model for EGPA, this mutant will provide an invaluable research tool to understand the molecular and pathogenic mechanisms of eosinophil-related vasculitis and its related organ damage. And, as the genes for this complex disease are not known, this mutant also affords a unique opportunity to delineate the multi-gene interactions causing EGPA.